(R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalenemethane amine (herein “Cinacalcet” or “CNC”) has a CAS number of 226256-56-0, a formula of C22H22F3N and the following structure:

This molecule is the free base form of Cinacalcet hydrochloride (herein “CNC-HCl”), having a CAS number of 364782-34-3 and the following structure:

CNC-HCl is marketed as SENSIPAR™, and is the first drug in a class of compounds known as calcimimetics to be approved by the FDA.
Calcimimetics are a class of orally active, small molecules that decrease the secretion of PTH by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of parathyroid hormone (PTH), an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death. As a calcimimetic, CNC-HCl is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with CNC-HCl lowers serum levels of PTH as well as the calcium/phosphorus ion product, a measure of the amount of calcium and phosphorus in the blood.
U.S. Pat. No. 6,011,068 discloses inorganic ion receptor activity, especially calcium receptor-active molecules, such as those having the general structure of Cinacalcet.
U.S. Pat. No. 6,211,244 discloses calcium receptor-active compounds related to Cinacalcet and methods of making such compounds. In accordance with the patent, Cinacalcet may be produced by reacting 1-acetyl naphthalene with 3-[3-(trifluoromethyl)phenyl]propylamine in the presence of titanium isopropoxide to produce an imine corresponding to Cinacalcet, followed by treatment with methanolic sodium cyanoborohydride and resolution of the racemic Cinacalcet base by chiral liquid chromatography, according to Scheme 1:

Similarly, using the process disclosed in U.S. Pat. No. 6,211,244, as well as DRUGS OF THE FUTURE (2002) 27 (9): 831 the desired Cinacalcet enantiomer may be produced by reacting (R)-1-(1-naphthyl)ethylamine with 3-[3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium isopropoxide to produce the imine that corresponds to Cinacalcet, followed by treatment with ethanolic sodium cyanoborohydride, according to the following scheme:

U.S. Pat. No. 6,211,244 discloses an additional process for the synthesis of Cinacalcet. This process involves treating 3-trifluoromethylcinnamonitrile, which can be prepared as disclosed in U.S. Pat. No. 4,966,988, with diisobutyl aluminum hydride, followed by treating the intermediate aluminum-imine complex with (R)-1-(1-naphthyl)ethylamine, and reducing the intermediate imine with ethanolic sodium cyanoborohydride, according to the following Scheme 3:

These three processes however, require the use of reagents such as titanium isopropoxide which is highly hygroscopic and expensive, as well as toxic, and ethanolic or methanolic sodium cyanoborohydride, which is highly toxic and flammable, and not environmentally friendly, making the processes difficult to apply on industrial scale. In addition, the description of these processes is not detailed.
Moreover, the only synthetic route known for the precursor of the process described in Scheme 2, namely the 3-[3-(trifluoromethyl)phenyl]propionaldehyde (FMPP) is disclosed in footnote 12 of Tetrahedron Letters (2004) 45: 8355 and is described in Scheme 4:
wherein reduction of the double bond of the corresponding Cinnamic acid derivative, followed by reduction of the carboxylic acid moiety to the corresponding alcohol, which is then oxidized to the aldehyde by Swern-oxidation. The Swern-oxidation reaction involves the use of reagents, such as oxalyl chloride and DMSO, which are not environmentally friendly and does not result in high yield, making the process arduous to apply on industrial scale.
Thus, an alternative process for the preparation of cinacalcet base and cinacalcet salt, which is more direct, higher yield, environmental friendly and applicable to industrial scale production is desirable. The present invention provides such an alternative.